chr5-13791994-ATTTGGTTC-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001369.3(DNAH5):βc.8440_8447delβ(p.Glu2814Ter) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000167 in 1,612,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E2814E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001369.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.8440_8447del | p.Glu2814Ter | frameshift_variant, splice_region_variant | 50/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.8440_8447del | p.Glu2814Ter | frameshift_variant, splice_region_variant | 50/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.8395_8402del | p.Glu2799Ter | frameshift_variant, splice_region_variant | 50/79 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250882Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135640
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1459854Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 726390
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Glu2814*) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is present in population databases (rs755136231, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826, 16627867, 22416021, 25186273). This variant is also known as p.Glu2814fs*1. ClinVar contains an entry for this variant (Variation ID: 454808). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2022 | The c.8440_8447delGAACCAAA pathogenic mutation, located in coding exon 50 of the DNAH5 gene, results from a deletion of 8 nucleotides at nucleotide positions 8440 to 8447, causing a translational frameshift with a predicted alternate stop codon (p.E2814*). This mutation, also referred to as 2814fsX1, was described as homozygous in an individual whose respiratory cilia showed absence of outer dynein arms under electron microscopy analysis (Olbrich H et al, Nat. Genet. 2002 Feb; 30(2):143-4). Subsequent immunofluorescent studies of this individual's respiratory epithelial cells suggested that this alteration lead to protein mislocalization (Fliegauf M et al, Am. J. Respir. Crit. Care Med. 2005 Jun; 171(12):1343-9). This alteration was also identified in trans with a pathogenic DNAH5 mutation (p.R3539H) in an individual with a similar absence of outer dynein arms (Djakow J et al. Pediatr Pulmonol, 2012 Sep;47:864-75). Additionally, this variant was detected in an individual who had another frameshift mutation (c.10815delT) and showed abnormal ciliary beat patterns (Raidt J et al, Eur. Respir. J. 2014 Dec; 44(6):1579-88), as well as in an individual with inner dynein arm and outer dynein arm defects who had a DNAH5 nonsense mutation (p.R2677*) along with the c.8440_8447delGAACCAAA mutation (Djakow J et al. Pediatr Pulmonol, 2016 May;51:498-509). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Mar 13, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Dec 11, 2023 | ACMG: PVS1, PM2, PM3, PP5 - |
Primary ciliary dyskinesia 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 05, 2018 | The DNAH5 c.8440_8447delGAACCAAA (p.Glu2814Ter) frameshift variant has been reported in five individuals with primary ciliary dyskinesia, including in one who carried the variant in a homozygous state, in three who carried the variant in a compound heterozygous state, and in one who carried the variant in a heterozygous state where a second variant was not identified, and also in a heterozygous state in an unaffected parent of a patient (Olbrich et al. 2002; Hornef et al, 2006; Djakow et al. 2012; Raidt et al. 2014; Djakow et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000063 in the European (non-Finnish) population from the Genome Aggregation Database. In respiratory epithelial cilia from an individual homozygous for the p.Glu2814Ter variant, expression of DNAH5 was observed at the ciliary base and the cilia were immotile, whereas expression of DNAH5 in controls was observed along the entire length of the axoneme (Fliegauf et al. 2005). Based on the evidence and due to the potential impact of frameshift variants, the p.Glu2814Ter variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 02, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Aug 29, 2022 | PVS1, PP4, PM2_SUP - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at